Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized, open-label, parallel-group, dose-ranging study.

The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to methotrexate. In this open-label, phase 2 study, 70 patients fulfilling American College of Rheumatology (ACR) criteria and negative for latent tuberculosis were randomized to four arms: 0.2, 0.4, or 0.8 mg/kg itolizumab weekly combined with oral methotrexate, and methotrexate alone (2:2:2:1). Patients were treated for 12 weeks, followed by 12 weeks of methotrexate alone during follow-up. Twelve weeks of itolizumab therapy was well tolerated. Forty-four patients reported adverse events (AEs); except for six severe AEs, all others were mild or moderate. Infusion-related reactions mainly occurred after the first infusion, and none were reported after the 11th infusion. No serum anti-itolizumab antibodies were detected. In the full analysis set, all itolizumab doses showed evidence of efficacy. At 12 weeks, 50 % of the patients achieved ACR20, and 58.3 % moderate or good 28-joint count Disease Activity Score (DAS-28) response; at week 24, these responses were seen in 22 and 31 patients. Significant improvements were seen in Short Form-36 Health Survey and Health Assessment Questionnaire Disability Index scores. Overall, itolizumab in combination with methotrexate was well tolerated and efficacious in RA for 12 weeks, with efficacy persisting for the entire 24-week evaluation period. (Clinical Trial Registry of India, http://ctri.nic.in/Clinicaltrials/login.php , CTRI/2008/091/000295).

Efficacy and safety of itolizumab, a novel anti-CD6 monoclonal antibody, in patients with moderate to severe chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, phase-III study.

BACKGROUND: Itolizumab, a humanized monoclonal antibody to CD6, is a novel therapeutic agent evaluated in chronic plaque psoriasis. OBJECTIVE: We sought to assess the safety and efficacy of itolizumab in moderate to severe chronic plaque psoriasis. METHODS: A total of 225 patients were randomized (2:2:1) to 2 different itolizumab arms (A or B; A = 4-week loading dose of 0.4 mg/kg/wk followed by 1.6 mg/kg every 2 weeks; B = 1.6/mg every 2 weeks) or placebo. At week 12, the placebo arm was switched to 1.6 mg/kg itolizumab every 2 weeks. The primary end point was the proportion of patients with at least 75% improvement in Psoriasis Area and Severity Index score at week 12. RESULTS: At week 12, 27.0% in arm A (P = .0172 vs placebo), 36.4% in B (P = .0043 vs placebo), and 2.3% in the placebo arm had at least 75% improvement in Psoriasis Area and Severity Index score. At week 28, the proportion with at least 75% improvement in Psoriasis Area and Severity Index score was comparable: 46.1%, 45.5%, and 41.9% for A, B, and placebo, respectively. In weeks 1 to 12, the incidence of all adverse events was comparable across arms (A, 43%; B, 38%; placebo, 47%) and the incidence of infections was not greater than placebo (11.1%, 8.9%, and 18.6% for A, B, and placebo). LIMITATIONS: No active comparator is a limitation. CONCLUSIONS: Itolizumab is an effective and well-tolerated novel biological therapy in moderate to severe psoriasis.

Induction of colony morphology variation in Rhodotorula gracilis by UV irradiation.

Nonlethal UV irradiation induced an unusually high frequency of colony morphology variation in Rhodotorula gracilis. The variation was not fixed but indicated further variability in subsequent platings. Microscopic examination of the cultures indicated that UV-irradiated variants had grossly varying types of shapes and arrangements of cells in contrast to the uniformly shaped and budding cells of the nonirradiated culture. Flow-cytometric analysis of a colony variant suggested a slightly higher proportion of cells with variable DNA content than the nonirradiated culture. Extensive biochemical characterization revealed only one difference in that the nonirradiated culture had a partial requirement for pantothenate while the colony variant was completely independent of this requirement. We speculate that UV triggers a yet unstudied means of variability in R. gracilis with possible accompanying recombinational events.

MIG1 overexpression causes flocculation in Saccharomyces cerevisiae.

MIG1, encoding a C2H2 zinc-finger repressor protein involved in carbon catabolite repression, was found to play a role in non-sexual flocculation of Saccharomyces cerevisiae. Disruption of MIG1 in a flocculent mutant strain of NCYC 227, resulted in a non-flocculent phenotype. Expression of MIG1 on a 2 mu pRS426 vector in a non-flocculent strain, YM 4134, caused flocculation; MIG1 on a high-copy-number LEU2-d plasmid caused intense flocculation in the same strain. Mutations in the SSN6 and TUP1 genes confer a flocculent phenotype in non-flocculent strains of S. cerevisiae, and it has been shown that Mig1 can tether the Ssn6p-Tup1p complex to the regulatory regions of glucose-repressible genes. Mutations in tup1 in a MIG1 background caused flocculation while double mutants of TUP1 and MIG1 did not flocculate. Based on these results, a model for the role of MIG1 in flocculation gene regulation is proposed.

Mitochondrial NADH dehydrogenase activity and ability to tolerate acetaldehyde determine faster ethanol production in Saccharomyces cerevisiae.

In rapidly fermenting yeast, the rotenone insensitive mitochondrial NADH dehydrogenase was not completely repressed by high glucose. This activity appeared to enhance the glycolytic rate due to which acetaldehyde accumulated intracellularly. To overcome the toxicity of acetaldehyde, the strain produced stress proteins. During late stationary phase of growth, the accumulated acetaldehyde was converted to ethanol resulting in faster ethanol production.

Congenital Lobar emphysema.

Congenital lobar emphysema is a rare but important clinical entity which may come to the paediatrician as an acute respiratory emergency. This is defined as a post-natal over-distension of one or more lobes of a histologically normal lung. To the best of our knowledge, this condition has not been reported in Indian Medical Literature to-date. Not that the actual incidence of Congenital Lobar Emphysema has changed materially but increased clinical awareness of the possibility of the diagnosis and the widespread use of roentgenography in infants has clearly resulted in frequent recognition of this condition. The plain x-ray study is so characteristic that an immediate diagnosis can be made for further line of management.

Ectopia in unduplicated ureters in children.

The clinico-pathological features and surgical management of 19 unduplicated ectopic ureters in 15 children are presented with special reference to the problems of recognition and treatment and to the underlying embryological and pathological significance of the wide-ranging associated abnormalities. The high incidence of renal and ureteric malformations, both ipsilateral and contralateral, is emphasised, as is also the frequent co-existence of vesical, bladder neck, urethral, genital and anal abnormalities. These associated anomalies modify the presentation of unduplicated ureteric ectopia and may mask its presence. Late recognition is common, but may be avoided by awareness of the problem. Whereas the degree of kidney involvement seems to dictate the choice and priorities of surgical treatment, the lower urinary tract anomalies have more significance as regards continuing disability and these largely determine the outcome in relation to continence.